Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Anti-obesity effects of the combined administration of CB1 receptor antagonist rimonabant and melanin-concentrating hormone antagonist SNAP-94847 in diet-induced obese mice

International Journal of Obesity volume 37, pages 279–287 (2013)Cite this article

Subjects

Abstract

OBJECTIVE:

Current anti-obesity monotherapies have proven only marginally effective and are often accompanied by adverse side effects. The cannabinoid 1 (CB1) receptor antagonist rimonabant, while effective at producing weight loss, has been discontinued from clinical use owing to increased incidence of depression. This study investigates the interaction between the cannabinoid and melanin-concentrating hormone (MCH) systems in food intake, body weight control, and mood.

DESIGN:

Lean male C57BL/6 mice were injected i.p. with rimonabant (0.0, 0.03, 0.3 and 3.0 mg kg−1) or the MCH1-R antagonist SNAP-94847 (0.0, 1.0, 5.0 and 10.0 mg kg−1) to establish dose response parameters for each drug. Diet-induced obese (DIO) mice were given either vehicle, sub-threshold dose of rimonabant and SNAP-94847 alone or in combination. Impact on behavioral outcomes, food intake, body weight, plasma metabolites and expression of key metabolic proteins in the brown adipose tissue (BAT) and white adipose tissue (WAT) were measured.

RESULTS:

The high doses of rimonabant and SNAP-94847 produced a reduction in food intake after 2 and 24 h. Combining sub-threshold doses of rimonabant and SNAP-94847 produced a significantly greater loss of body weight in DIO mice compared with vehicle and monotherapies. In addition, combining sub effective doses of these drugs led to a shift in markers of thermogenesis in BAT and lipid metabolism in WAT consistent with increased energy expenditure and lipolysis. Furthermore, co-administration of rimonabant and SNAP-94847 produced a transient reduction in food intake, and significantly reduced fat mass and adipocyte size. Importantly, SNAP-94847 significantly attenuated the ability of rimonabant to reduced immobility time in the forced swim test.

CONCLUSION:

These results provide proof of principle that combination of rimonabant and a MCH1 receptor antagonist is highly effective in reducing body weight below that achieved by rimonabant and SNAP-94847 monotherapies. In addition, the combination therapy normalizes the rimonabant-induced behavioral changes seen in the forced swim test.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Cooke D, Bloom S . The obesity pipeline: current strategies in the development of anti-obesity drugs. Nat Rev Drug Discov 2006; 5: 919–931.

    Article  CAS  Google Scholar 

  2. Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 1994; 350: 240–244.

    Article  CAS  Google Scholar 

  3. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ . Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348: 1625–1638.

    Article  Google Scholar 

  4. Despres JP, Golay A, Sjostrom L . Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121–2134.

    Article  CAS  Google Scholar 

  5. Di Marzo V, Goparaju SK, Wang L, Liu J, Batkal S, Jaral Z et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001; 410: 822–825.

    Article  CAS  Google Scholar 

  6. Hubert HB, Feinleib M, McNamara PM, Castelli WP . Obesity as an independent risk factor for cardiovascular disease: A 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983; 67: 968–977.

    Article  CAS  Google Scholar 

  7. Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, DeLeon J, Lagu B et al. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med 2002; 8: 825–830.

    Article  CAS  Google Scholar 

  8. Verty ANA, Allen AM, Oldfield BJ . The Endogenous Actions of Hypothalamic Peptides on Brown Adipose Tissue Thermogenesis in the Rat. Endocrinology 2010; 151: 4236–4246.

    Article  CAS  Google Scholar 

  9. Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E . Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 1998; 396: 670–674.

    Article  CAS  Google Scholar 

  10. Georgescu D, Sears RM, Hommel JD, Barrot M, Bolaños CA, Marsh DJ et al. The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J Neurosci 2005; 25: 2933–2940.

    Article  CAS  Google Scholar 

  11. Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest 2003; 112: 423–431.

    Article  CAS  Google Scholar 

  12. Huang H, Acuna-Goycolea C, Li Y, Cheng HM, Obrietan K, van den Pol AN . Cannabinoids excite hypothalamic melanin-concentrating hormone but inhibit hypocretin/orexin neurons: implications for cannabinoid actions on food intake and cognitive arousal. J Neurosci 2007; 27: 4870–4871.

    Article  CAS  Google Scholar 

  13. Verty ANA, Boon WM, Mallet PE, McGregor IS, Oldfield BJ . Involvement of hypothalamic peptides in the anorectic action of the CB receptor antagonist rimonabant (SR 141716). Eur J Neurosci 2009; 29: 2207–2216.

    Article  Google Scholar 

  14. Verty ANA, Allen AM, Oldfield BJ . The effects of rimonabant on brown adipose tissue in rat: implications for energy expenditure. Obesity 2009; 17: 254–261.

    Article  CAS  Google Scholar 

  15. Stefanidis A, Verty ANA, Allen AM, Owens NC, Cowley MA, Oldfield BJ . The role of thermogenesis in antipsychotic drug-induced weight gain. Obesity 2009; 17: 16–24.

    Article  CAS  Google Scholar 

  16. Verty ANA, McFarlane JR, McGregor IS, Mallet PE . Evidence for an interaction between CB1 cannabinoid and melanocortin MCR-4 receptors in regulating food intake. Endocrinology 2004; 145: 3224–3231.

    Article  CAS  Google Scholar 

  17. Verty ANA, McGregor IS, Mallet PE . Consumption of high carbohydrate, high fat, and normal chow is equally suppressed by a cannabinoid receptor antagonist in non-deprived rats. Neurosci Lett 2004; 354: 217–220.

    Article  CAS  Google Scholar 

  18. Verty ANA, McGregor IS, Mallet PE . Evidence for an interaction between CB1 cannabinoid and oxytocin receptors in food and water intake. Neuropharmacology 2004; 47: 593–603.

    Article  CAS  Google Scholar 

  19. Verty ANA, Singh ME, McGregor IS, Mallet PE . The cannabinoid receptor antagonist SR 141716 attenuates overfeeding induced by systemic or intracranial morphine. Psychopharmacology 2003; 168: 314–323.

    Article  CAS  Google Scholar 

  20. Bermudez-Silva FJ, Viveros MP, McPartland JM, Rodriguez de Fonseca F . The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning? Pharmacol Biochem Behav 2010; 95: 375–382.

    Article  CAS  Google Scholar 

  21. Pissios P . Animals models of MCH function and what they can tell us about its role in energy balance. Peptides 2009; 30: 2040–2044.

    Article  CAS  Google Scholar 

  22. Cannon B, Nedergaard J . Brown adipose tissue: Function and physiological significance. Physiol Rev 2004; 84: 277–359.

    Article  CAS  Google Scholar 

  23. Saely CH, Geiger K, Drexel H . Brown versus White Adipose Tissue: A Mini-Review. Gerontology 2012; 58: 15–23.

    Article  Google Scholar 

  24. Quarta C, Bellocchio L, Mancini G, Mazza R, Cervino C, Braulke LJ et al. CB(1) signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance. Cell Metab 2010; 11: 273–285.

    Article  CAS  Google Scholar 

  25. Jo YH, Chen YJ, Chua SCJ, Talmage DA, Role LW . Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit. Neuron 2005; 48: 1055–1066.

    Article  CAS  Google Scholar 

  26. Lihn AS, Jessen N, Pedersen SB, Lund S, Richelsen B . AICAR stimulates adiponectin and inhibits cytokines in adipose tissue. Biochem Biophys Res Commun 2004; 316: 853–858.

    Article  CAS  Google Scholar 

  27. Perwitz N, Wenzel J, Wagner I, Büning J, Drenckhan M, Zarse K et al. Cannabinoid type 1 receptor blockade induces transdifferentiation towards a brown fat phenotype in white adipocytes. Diabetes Obes Metab 2010; 12: 158–166.

    Article  CAS  Google Scholar 

  28. Thornton C, Sardini A, Carling D . Muscarinic receptor activation of AMP-activated protein kinase inhibits orexigenic neuropeptide mRNA expression. J Biol Chem 2008; 283: 17116–17122.

    Article  CAS  Google Scholar 

  29. Kahn BB, Flier JS . Obesity and insulin resistance. J Clin Invest 2000; 106: 473–481.

    Article  CAS  Google Scholar 

  30. Kim JY, Nolte LA, Hansen PA, Han DH, Ferguson K, Thompson PA et al. High-fat diet-induced muscle insulin resistance: relationship to visceral fat mass. Am J Physiol Regul Integr Comp Physiol 2000; 279: R2057–R2065.

    Article  CAS  Google Scholar 

  31. Sindelka G, Skrha J, Prázn M, Haas T . Association of obesity, diabetes, serum lipids and blood pressure regulates insulin action. Physiol Res 2002; 51: 85–91.

    CAS  PubMed  Google Scholar 

  32. Heiling VJ, Miles JM, Jensen MD . How valid are isotopic measurements of fatty acid oxidation? Am J Physiol Regul Integr Comp Physiol 1991; 261: E572–E577.

    CAS  Google Scholar 

  33. Jensen MD . Diet effects on fatty acid metabolism in lean and obese humans. Am J Clin Nutr 1998; 67 (3 Suppl): 531S–534S.

    Article  CAS  Google Scholar 

  34. Marchesini G, Moscatiello S, Di Domizio S, Forlani G . Obesity-associated liver disease. J Clin Endocrinol Metab 2008; 93 (11 Suppl 1): S74–S80.

    Article  CAS  Google Scholar 

  35. Johansson K, Neovius K, DeSantis SM, Rössner S, Neovius M . Discontinuation due to adverse events in randomized trials of orlistat, sibutramine and rimonabant: A meta-analysis. Obes Rev 2009; 10: 564–575.

    Article  CAS  Google Scholar 

  36. André A, Gonthier MP . The endocannabinoid system: Its roles in energy balance and potential as a target for obesity treatment. Int J Biochem Cell Biol 2010; 42: 1788–1801.

    Article  Google Scholar 

  37. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 1990; 87: 1932–1936.

    Article  CAS  Google Scholar 

  38. Sears RM, Liu RJ, Narayanan NS, Sharf R, Yeckel MF, Laubach M et al. Regulation of nucleus accumbens activity by the hypothalamic neuropeptide melanin-concentrating hormone. J Neurosci 2010; 30: 8263–8273.

    Article  CAS  Google Scholar 

  39. Kalueff AV, Wheaton M, Murphy DL . What's wrong with my mouse model? Advances and strategies in animal modeling of anxiety and depression. Behav Brain Res 2007; 179: 1–18.

    Article  CAS  Google Scholar 

  40. Takahashi E, Katayama M, Niimi K, Itakura C . Additive subthreshold dose effects of cannabinoid CB(1) receptor antagonist and selective serotonin reuptake inhibitor in antidepressant behavioral tests. Eur J Pharmacol 2008; 589: 149–156.

    Article  CAS  Google Scholar 

  41. Tzavara ET, Davis RJ, Perry KW, Li X, Salhoff C, Bymaster FP et al. The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions. Br J Pharmacol 2003; 138: 544–553.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the National Health and Medical Research Council to Prof Oldfield and Dr Verty (Grant Number: 3160479). ANAV is the recipient of the National Health and Medical Research Council (NHMRC) Peter Doherty Postdoctoral Research Fellowship.

Author information

Authors and Affiliations

  1. Department of Physiology, Monash University, Clayton, Victoria, Australia

    A N A Verty, S H Lockie, A Stefanidis & B J Oldfield

Authors
  1. A N A Verty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S H Lockie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Stefanidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B J Oldfield
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B J Oldfield.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verty, A., Lockie, S., Stefanidis, A. et al. Anti-obesity effects of the combined administration of CB1 receptor antagonist rimonabant and melanin-concentrating hormone antagonist SNAP-94847 in diet-induced obese mice. Int J Obes 37, 279–287 (2013). https://doi.org/10.1038/ijo.2012.35

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2012.35

Keywords

This article is cited by

Search

Advanced search

Quick links